This application requests funding for the study coordination, data management, and biostatistical support for a Phase III clinical trial of creatine in Huntington's disease (HD). This is a companion application to that of Steven M. Hersch, MD, PhD, from Massachusetts General Hospital (MGH), entitled Creatine Safety, Tolerability &Efficacy (CREST-E). HD is an autosomal dominant, uniformly progressive neurodegenerative disorder characterized clinically by movement disorders, personality changes, and cognitive impairment. Approximately 30,000 people in the United States have clinical manifestations of HD, and an additional 150,000 healthy people are thought to be at immediate risk for developing HD. There are no effective treatments for HD and HD progresses relentlessly causing disability and death. Evidence from mouse models of HD and human studies suggests that creatine may slow the course of HD in a dose dependent manner. Pilot data on serum and brain bioavailability, tolerability, HD signs and symptoms, and biomarkers indicate that 30-grams daily of creatine is an optimal dose. We propose to test the hypothesis that creatine can slow the decline of HD by conducting a randomized, double-blinded, placebo-controlled, parallel group trial of 30 grams daily of creatine in 650 symptomatic individuals with HD. The primary outcome variable will be the change from baseline to Month 36 in the Total Functional Capacity (TFC) score. The study will have 96% power to detect a clinically relevant 25% slowing in TFC. The trial will be conducted under the auspices of the Huntington Study Group (HSG) at approximately 42 sites worldwide. This project is consistent with the NCCAM mission of exploring alternative therapies such as creatine with scientifically rigorous studies. There are important public health implications of this study. If the study is positive, it would be a breakthrough in HD research that would change HD clinical care and would spur research into similar compounds for a host of related neurodegenerative diseases. Additionally, the study will provide critical information on the long-term safety of high dose creatine, which is widely used among healthy athletes and patients with a variety of neurodegenerative disorders and other diseases. This will allow NCCAM to distribute authoritative information to the public about the safety of creatine.